Recent evidence has shown that cytotoxic T lymphocytes (CTLs) specific for surface modifications on autologous cells play a critical role in the effector mechanisms important in the destruction of tumors and in autoimmunity. Precise analysis of the cell-cell interactions, homeostatic regulation and genetic principles governing the generation of these CTLs in man has been facilitated by 1) the development of in vitro techniques for the sensitization of human lymphocytes to major histocompatibility complex (MHC) identical leukemic cells and to chemically modified (e.g., TNP-modified) autologous cells and 2) the development of methods for the isolation of functionally unique subclasses of human T cells. Thus, we have shown that human T cells can be triggered in vitro by MHC identical leukemic blasts or TNP-modified autologous cells to differentiate into CTLs which specifically lyse 51Cr labelled target cells bearing surface antigens in common with the stimulating cell. Further, this differentiation process is facilitated by helper signals provided by interaction with either allogeneic cells or soluble antigens. Our objectives in this grant are to 1) investigate in detail the role of human T cell subclass interactions in the induction and homeostatic control of the differentiation of CTLs which specifically recognize altered surface determinants on autologous cells and determine whether more than one T cell subclass is required and whether suppressor or helper cells modulate this response; 2) study the mechanisms by which regulatory signals facilitate the induction of altered-self reactive CTLs; 3) investigate the nature of target cell surface antigens recognized by MHC identical CTLs, and determine whether these killer cells recognize, at least in part, target cell MHC determinants; and 4) extend these studies to the analysis of T cell mediated altered-self cytolysis in patients with leukemia and in patients with autoimmune diseases.